Mouse mammary tumor virus (MMTV) was the first virus shown to cause cancer in mammals and is transmitted through milk. MMTV has long been studied as a prototype for viruses that are acquired through the gut- associated lymphoid tissue or GALT. MMTV contains a viral protein, called the superantigen (Sag), that enables it to infect lymphoid cells, first in the gut and then systematically. We believe that this allows MMTV to spread from the gut to the mammary gland via infected lymphocytes. One of the goals of this project is to determine specifically which type of lymphocytes are important for delivery MMTV to the mammary cell and how they accomplish this transfer. Trafficking of infected lymphocytes to the mammary gland will be studied in vivo and the effects of disrupting this trafficking on virus transfer to this tissue will be examined, using antibody blocking techniques and beta7-integrin/L-selectin knockout mice that have disrupted homing of lymphocytes to mucosal tissue. We will also use genetically-marked viruses to look at the specific lymphocyte subsets that are infected and to determine how virus transfer between different cells occur. In addition to MMTV's interaction with lymphoid cells at early stages of infection, be believe that this virus also subverts the immune system at later stages and this ultimately affects its ability to cause mammary tumors. Thus, another aim of this proposal is to determine whether MMTV induces immune tolerance and whether Sag- mediated deletion of T cells plays a role in this process. Because mice are currently the best genetically-manipulatable and immunologically well- characterized species available, our studies on how MMTV utilizes and subverts the immune system will further our understanding of the relationship between the cell type, site of infection and host response to retroviral infection.